Progress in Lupus Trial Design

Contact: Mark.Abrahams@ig-b.com

Patients

Trial design

Interventions Endpoints

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3 key design factors determine the fate of clinical trials

Challenges in SLE trial design

We are learning as we go

Patients

• Lupus is a heterogenous disease

• Patients must be sick enough to see treatment effect

• Active disease vs inactive disease?• Impact on endpoint

(index vs flare)• Trial length: flare trials

(in inactive dz pts) take several years longer; Difficult to keep pts on same background

Interventions

• Unethical to randomize patients with active disese to placebo alone

• Background treatments muddy the picture

Endpoints

• Disease activity indices a work in progress

• Difficult to correlate biomarkers with clinical outcome (in nonrenal SLE)

• Length of study: longer trials may be needed to see efficacy in joint/organ damage

Some nomenclature: BILAGB

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BILAG B: Moderate disease activity requiring any of the below:

• Systemic low dose oral glucocorticoids (equivalent to prednisolone ≤ 20 mg/day• Intramuscular or intra-articular or soft tissue glucocorticoids injection (equivalent to

methylprednisolone < 500mg)• Topical glucocorticoids• Topical immunomodulators• Antimalarials or thalidomide or prasterone or acitretin• Symptomatic therapy (eg: NSAIDs for inflammatory arthritis)

BILAG A: Severe disease activity requiring any of the below:

• Systemic high dose oral glucocorticoids (equivalent to prednisolone > 20 mg/day)• Intravenous pulse glucocorticoids (equivalent to pulse methylprednisolone ≥ 500 mg)• Systemic immunomodulators (biologics, immunoglobulins and plasmapheresis)• Therapeutic high dose anticoagulation in the presence of high dose steroids or

immunomodulators (eg: warfarin with target INR 3 – 4)

BILAG C: Mild disease

BILAG E: System never involved

BILAG D: Inactive disease but previously affected

Some nomenclature: SLEDAI

Rituximab failed P3 trials

Much literature documents rituximab efficacy in severe refractory SLE

A review in 188 SLE patients from 35 studies (mostly open-label) reported efficacy rates ~90%

However, two large randomized trials were unexpectedly negative

EXPLORER: RTX for non-renal SLE•Patients: moderate-to-severe active disease (at least one BILAG A or two BILAG B)•Intervention: background of single immunosuppressant, (AZT, MMF, or MTX), plus steroids•Endpoint: Major clinical response (MCR) - BILAG C in all organ systems without new flares•Results: No significant difference between groups, however, sub-group analysis showed benefit in African Americans, hispanics, anti-dsDNA and complementLUNAR: RTX in lupus nephritis•Intervention: Background of steroids, Cytoxan and/or MMF. •Endpoint: Creatinine, proteinuria, and urine sediment •Results: no significant difference between groups, however,

• African American and Hispanic subgroups with better response (not statistically significant)

Why might a beneficial effect have been missed?

• Easy-fo-fail endpoint: BILAG (mild flare)• Most EXPLORER patients had mild disease; patients with severe disease were under represented• Patients received high doses of background steroids and immunosuppressants• EXPLORER lasted 52 weeks. Open-label studies have shown maximal benefit out to 18 months

An easy-to-fail endpoint and aggressive background meds

Abatacept failed P2 trial

An easy-to-fail endpoint and aggressive background meds

Belimumab failed P2 trial

Design

• Patients: Clinically active disease as defined by SLE-DAI≥4; no serologic requirements• Intervention: Standard of care (steroids and immunosuppressants) in addition to

belimumab• Endpoint: Co-primary endpoints included percentage change in the SELENA SLEDAI,

and time to flare [defined by SELENA–SLEDAI flare index (SFI)]• Results: No significant difference between groups, however, Benefits were seen in the

seropositive sub-group. Significant improvements in B cell counts, immunoglobulin levels, anti-dsDNA antibody levels, and complement

Why might a beneficial effect have been missed?

• Seronegative patients included in the study (some chronic disease features may have been misinterpreted as active inflammation)

• Unlimited changes in corticosteroid doses and immunosuppressants, confounding the disease activity assessments.

• Disease indices perhaps not sensitive enough

An easy-to-fail endpoint and aggressive background meds

What would’ve happened had they used different endpoints?

BILAG A flares are a more sensitive endpoint than BILAG B or C flares

• Significant benefit for both rituximab and abatacept patients (post hoc reanalysis)

• Using BILAG A (severe flare) as the primary endpoint

• Vs the mild-moderate C or B flare definitions used in the actual P2 studies

• Use caution interpreting post hoc analyses

Reduced risk of

BILAG A flare

HR=0.61P=0.052

Reduced risk of

BILAG A flare

HR=0.61P=0.052

Rituximab results - different flare definitions

Abatacept results - different flare definitions

BLISS (belimumab-P3) trial design incorporated learnings from previous studies

Success

Epratuzumab P2 trials also used novel/refined trial design approaches

Success

BICLA: BILAG-based Combined Lupus Assessment

• Measuring efficacy in terms of joint/organ protection or steroid sparing effects will require substantially longer trials (3-5 years)

Evolution of trial design in SLE

Ongoing late stage trials

All are baking the same cake, but each recipe is slightly different

Patients Intervention Endpoints

LY2127399 (ILLUMINATE)

P3

Active disease: SLEDAI≥6,

ANA+

SOC (“with some restrictions in dose

adjustments”)SRI

epratuzumab(EMBODY2)

P3

Active mod-severe SLE via BILAG

and SLEDAISOC BICLA and no

in background meds

atacicept(APRIL SLE)

P3BILAG A or B SOC BILAG A or B flare

abatacept(ACCESS)

P2Lupus nephritis

Abatacept + Cytoxan + AZT vs

Cytoxan + AZT

GFR, proteinuria, creatinine

Thank You